Viral infections of the gastrointestinal (GI) tract are a worldwide cause of morbidity and mortality. However, little is known about the mechanisms involved in GI viral infections. In order to devvelop strategies for vaccination and treatments, a basic understanding of the factors that influence the capacity of virus to replicate in the intestine is needed. The family Reoviridae includes both reoviruses and rotaviruses, a major cause of intestinal infection in man. Although reoviruses are not known to be associated with human disease, reovirus infection of mice and rats provides an excellent experimental model for the study of viral pathogenesis in the GI tract. Reovirus has been extensively studied and utilized in experimental model systems primarily because of its segmented double stranded RNA (dsRNA) genome. Genetic reassortants can be made between all three mammalian serotypes, allowing genetic analysis of pathogenic mechanisms. As the power of the genetic approach has been increasingly appreciated, the reovirus model has assumed additional importance. We plant to utilize reovirus reassortants to analyze the molecular basis of gastrointestinal infection. The following areas will be investigated: 1) The early interaction of virus with the gastrointestinal proteolytic environment in vivo the in simulated GI conditions in vitro. These studies will extend the observations that GI proteolytic enzymes provide a major barrier to infection by reovirus. The identification of the proteolytic enzymes that affect virus survival in the GI tract may lead to a new approach in chemotherapy. 2) The immune response to ingested virus. The capacity to generate a protective immune response is a central problem in research on vaccines for GI pathogens. These studies will examine the role of specific viral genes and the immune responsiveness in the generation of humoral immunity in the GI tract and viral pathogenesis. 3) The role of recombination in viral adaptation to the GI environment. Recombination of segmented viruses in the GI tract may play a crucial role in pathogenesis.